Checkpoints in the Cell Cycle Are Manned by Tumor Suppressors

The cell cycle machinery also has crucial “brake” mechanisms that function as checkpoints, as noted earlier. The com­ponents of the brake and checkpoint mechanisms were dis­covered by fusing a normal cell with a cancer cell of the same type, to form a hybrid cell with two nuclei.

Tumor suppressors play several different functional roles in braking and checking, and they can be divided into two broad types, gatekeepers and caretakers. Gatekeepers are genes and proteins that are involved in the actual checkpoint machinery connecting cell damage with a halt in the cell cycle. Thus, p53 (“protein of 53-kilodalton mass”) is a gatekeeper importantly involved in the pathway that detects DNA damage; it causes a halt in the cell cycle and, if the damage cannot be repaired, signals the cell to undergo programmed death. It is thought that about 50% of human cancers have a mutation in p53. Caretakers are usually proteins involved in the repair of dam­age or the normal maintenance of proteins crucial in the cell cycle. A human example of a caretaker gene and protein is BRCAl (“breast cancer 1”). This protein is normally involved in the repair of nucleotide mismatches (e.g., G paired with T rather than with C in the complementary DNA strand), and its mutant gene has been found to underlie familial (hereditary) breast cancer in some families.

With these normal functions, one can see how these genes and proteins would suppress tumor activity and cell pro­liferation. If they are working, DNA is repaired before the cell attempts to divide; this would tend to prevent mutation or other types of genetic instability. However, loss-of-function mutation in these genes means the cell now has lost the ability to detect or repair DNA damage. For example, when p53 is nonfunctional, even a badly damaged cell may not receive an adequate signal to commit suicide, and this already-mutant cell can continue to divide. Thus, tumor suppressor genes are associated with loss-of-function mutations in cancer, not gain-of-function mutations as for oncogenes. Returning to the automobile analogy of brakes, mutant tumor suppressor genes resemble dysfunctional braking systems, or no brakes at all.

We focus on two gatekeeper-type tumor suppressors because their role and importance in cancer are clear. The role of caretakers such as BRCAl is both more complex and more uncertain (see suggested reading on BRCA in the Bibliog­raphy).